Over 10,000 Americans fill prescriptions for nicotine gum each day. Since FDA approval 3 yr ago, about 1 million patients (30%) have stopped smoking with it, despite M.D.'s not knowing what dose (2mg or 4mg) or what schedule of taking gum (ad lib cigarette urge or on a regular time schedule, eg, q1h while awake) is most effective. Although recent, hman laboratory work from the NIDA ARC strongly indicates that a 4mg dose taken q1h while awake should produce the best treatment results, this hypothesis has not been clinically tested. In the proposed study we plan to determine the optimal nicotine gum dose & schedule to treat tobacco dependency. We shall randomly enter 400 male and female smokers into a 2x2 factorial treatment trial, crossing dose (2 vs 4mg) with medication schedule (ad lib vs q1h). Subjects will be stratified, before random assignment to 1 of 4 treatment conditions, by: 1) Baseline, cigarette smoking cotinine level: greater than 294 ng/ml (High dependent) or less than 294 ng/ml (Low dependent) & 2) Whether or not the subject has ever used 2mg nicotine gum before. Age, sex, smoking history, & other factors which could influence treatment results will be controlled for in the logistic regression analysis. After medical intake, subjects will be in Active Treatment for 3 mo followed by a 4 mo Tapering Phase. Then all subjects will be followed for 12 more mo to determine long-term smoking cessation results. The primary outcome measure will be sustained abstinence from cigarettes, objectively confirmed, for the entire 12 mo from the end of Tapering through the end of Follow-Up. Other dependent variables measured throughout the 19 mo trial include tobacco withdrawal symptoms, # gums used/day, serum nicotine & cotinine, amount of nicotine remaining in chewed gum, & mood state, among others. We shall examine our data to test the hypotheses: 1) Are high dependent smokers best treated with a 4mg dose taken q1h, but low dependent smokers best treated with 2mg taken as lib? 2) Does score on the Fagerstrom Nicotine Tolerance Scale predict best treatment condition? 3) Does better control of tobacco withdrawal symptoms during treatment increase quit rate? 4) Does closer match of serum cotinine during treatment to that when smoking increase quitting? 5) Can subjects regulate nicotine intake from gum to improve quit rate? Knowledge from this project should improve treatment results with nicotine gum, allowing better matching of treatment & subject conditions, thus further reducing the multibillion dollar, annual medical costs of cigarette produced diseases.